Our overall therapeutic goal is to develop a drug treatment that reduces suffering and improves quality of life for victims of peripheral neuropathies - a diverse group of neurological disorders with genetic, metabolic or toxic etiologies. Patients who suffer from peripheral neuropathy can experience loss of voluntary or involuntary motor function and a wide range of disordered sensations, including intense chronic pain. In peripheral neuropathies, demyelination of nerve axons is associated with loss of signal propagation that directly or indirectly causes the symptoms of the neuropathy. Exposure of specific voltage-gated potassium channels on nerve axons by demyelination creates a condition where the propagation of action potentials can be terminated by a "short circuit". Our mechanistic approach is to selectively block this specific class of voltage-gated potassium channels and restore axonal conduction in demyelinated peripheral nerves. In Phase I of the project, we successfully established the basic screening technologies, developed a focused chemical library of potassium channel blockers and identified lead molecules. In Phase II, we will study compounds from an expanded chemical library using in vitro assays and animal efficacy and safety "models" with the objective of selecting candidates for preclinical and clinical development. PROPOSED COMMERCIAL APPLICATION: Peripheral neuropathies afflict millions of people in the United States and tens of millions worldwide. For example, the NIDDK estimates that 16 million people in the US have diabetes and that 30-40% of diabetics have symptoms of peripheral neuropathy. In addition, certain drugs used in treating cancer cause an estimated 260,000 cases each year of peripheral neuropathy that can limit the use of the chemotherapeutic agents. There is no doubt that an effective drug treatment for the symptoms of peripheral neuropathy would have a substantial medical. societal and commercial impact.